You are on page 1of 11

Open Access Review

A literature review of cost-effectiveness


of intravenous recombinant tissue
plasminogen activator for treating acute
ischaemicstroke
Heesoo Joo,1 Guijing Wang,2 Mary G George2

To cite: JooH, WangG, ABSTRACT US$53.9billion in the USA and 64.1billion


GeorgeMG. A literature Background Intravenous recombinant tissue plasminogen in Europe.3 4 Approximately 70% of strokes
review of cost-effectiveness
activator (IV rtPA) is recommended treatment for patients are ischaemic worldwide, while the propor-
of intravenous recombinant
with acute ischaemic stroke, but the cost-effectiveness tion of ischaemic stroke varies by race/
tissue plasminogen activator for
treating acute ischaemic stroke. of IV rtPA within different time windows after the onset of ethnicity and region.1 5
Stroke and Vascular Neurology acute ischaemic stroke is not well reviewed.
To reduce the burden associated with stroke,
2017;0: e000063. doi:10.1136/ Aims To conduct a literature review of the cost-
svn-2016-000063 effectiveness studies about IV rtPA by treatment times. investigations of cost-effectiveness of available
Summary of review A literature search was conducted treatments for patients with stroke such as
using MEDLINE, EMBASE, CINAHL and Cochrane intravenous (IV) injection of recombinant
Received 13 December 2016 Library, with the keywords acute ischemic stroke, tissue plasminogen activator (rtPA) are necessary.
Revised 4 February 2017
Accepted 6 February 2017
plasminogen activator, cost, economic benefit, saving Since the US Food and Drug Administration
and incremental cost-effectiveness analysis. The review (FDA) approval in 1996, rtPA remains the
is limited to original research articles published during only thrombolytic agent approved for acute
19952016 in English-language peer-reviewed journals. ischaemic stroke in the USA.6 IV rtPA has
We found 16 studies meeting our criteria for this review.
been shown to improve health outcomes after
Nine of them were cost-effectiveness studies of IV rtPA
treatment within 03hours after stroke onset, 2 studies
stroke.7 8
within 34.5hours, 3 studies within 04.5hours and 2 In the past two decades, there have been
studies within 06hours. IV rtPA is a cost-saving or a cost- some cost-effectiveness studies on IV rtPA.
effectiveness strategy from most of the study results. Only For instance, Fagan etal showed that IV rtPA
one study showed incremental cost-effectiveness ratio within 3hours after the onset of stroke saved
of IV rtPA within 1 year was marginally above US$50000 cost associated with stroke treatment as well as
per quality-adjusted life year threshold. IV rtPA within improved outcomes from stroke in their 1998
03hours after stroke led to cost savings for lifetime or 30 study.9 Additionally, we found three review
years and IV rtPA within 34.5hours after stroke increased
articles on the cost-effectiveness of IV rtPA
costs but still was cost-effective.
for acute ischaemic stroke.1012 All of them
Conclusions The literature generally showed that IV rtPA
was a dominant or a cost-effective strategy compared with reviewed studies published prior to2008.1012
traditional treatment for patients with acute ischaemic Since the new guidelines of IV rtPA between
stroke without IV rtPA. The findings from the literature 3 and 4.5 hours after the onset of acute
lacked generalisability because of limited data and various ischaemic stroke from theAmerican Heart
assumptions. Association/American Stroke Association
(AHA/ASA) as well as similar new recommen-
INTRODUCTION dations from other organisations in Europe
Stroke is a serious brain injury that can or Australia were released in late 2000s and
result in permanent disability and death. early 2010s,1316 and the cost-effectiveness
The burden of stroke, including the abso- of IV rtPA for the extended time windows,
1
Division for Heart Disease and within 4.5hours after the onset of stroke, has
Stroke Prevention, CDC; IHRC
lute numbers of incidence and death,
increased during the last decade.1 Globally, never been examined, an up-to-date review
Inc., Atlanta, Georgia, USA
2
Division for Heart Disease and an estimated 33million strokes occurred and of economic impact of IV rtPA is needed to
Stroke Prevention, CDC, Atlanta, 5.8million individuals died from stroke in better understand the cost-effectiveness of
Georgia, USA 2010.1 2 In addition, around 5million stroke IV rtPA under various treatment conditions.
survivors have permanent disability.2 In 2010, Thus, we conducted a literature review of
Correspondence to
Dr Guijing Wang; gbw9@cdc. the estimated total cost of stroke, including cost-effectiveness of IV rtPA published up to
gov direct medical cost and indirect cost, was 2014.

 JooH, et al. Stroke and Vascular Neurology 2017;0:e000063. doi:10.1136/svn-2016-000063 1


Copyright 2017 by BMJ Publishing Group Ltd.
Open Access

Figure 1 Selection of studies on cost-effectiveness analysis of recombinant tissue plasminogen activator (rtPA) for acute
ischaemic stroke.

METHODS air transportation for patients with stroke, and thus were
We performed a comprehensive literature search of excluded. In addition, review articles, editorial letters,
peer-reviewed journal articles published in English abstracts and commentaries were excluded (n=8). We
between January 1995 and December 2016 by using the completed full-text review of all articles that passed the
databases MEDLINE, EMBASE, CINAHL and Cochrane initial titles and abstracts review and finalised the set of
Library. We augmented the search by using Google original research articles (n=16) for this study by further
Scholar and checking the references of the articles we excluding three studies that were not original cost-effec-
obtained. The strategy used for the search included tiveness studies. Cost-effective analysis is an economic
keywords in stroke and rtPA treatment including acute evaluation method comparing both costs and health
ischemic stroke, tissue plasminogen activator and rtPA, and outcomes of alternative interventions.17 Common health
keywords in cost-effectiveness analyses including cost, outcomes used in the literature include quality-adjusted
economic, benefit, effectiveness and ICER (incremental cost-effec- life years (QALYs), life years gained, number of cases
tiveness analysis). prevented and mortality.17 QALYs, which were developed
Figure1 depicts the process of literature selection in 1960s for cost-effectiveness analyses, are measures of
for this review. The initial search yielded 224 abstracts. health considering both mortality and morbidity. QALYs
By screening of titles and abstracts, 197 studies were are valued between 0 and 1 per year, meaning 0 as death
excluded because they were not cost-effectiveness studies and 1 as perfect health.18 Cost-effectiveness analysis using
or because they were about supporting strategies to QALYs is also called as cost-utility analysis.19 ICER, the
increase the usage of IV rtPA, such as telemedicine or main estimate in a cost-effectiveness analysis, is derived

2 JooH, et al. Stroke and Vascular Neurology 2017;0:e000063. doi:10.1136/svn-2016-000063


Open Access

Figure 2 Conceptual framework of cost-effectiveness of recombinant tissue plasminogen activator (rtPA) therapy. ICER,
incremental cost-effectiveness analysis; QALY, quality-adjusted life year.

by the difference in costs over the difference in health the estimated ICER and an ICER threshold. In this paper,
outcomes between alternative interventions. In this we used US$50000/QALY as a reference threshold.20 If
review, ICER is the difference in cost between IV rtPA- the estimated ICER is below the threshold, thatis, located
treated group and non-IV rtPA group, thatis, incremental under the dotted line in figure2, we define that IV rtPA
cost, over the differences in QALYs between them, thatis, is a cost-effective strategy and adopt the IV rtPA strategy.
incremental QALYs. To compare ICERs from different countries, we derived
We analysed the literature by1: model structure and 2014 US dollar value from all studies, which did not report
main data sources,2 study results and3 major limitations. ICERs in US dollars, by using consumer price indices
For model structure and data sources, we examined (CPI) from the World Bank and purchasing power parity
perspective, modelling method, and intervention type, (PPP) exchange rate in 2014 from the Organisation for
and main source of economic and clinical data. For study Economic Cooperation and Development (OECD).2123
results, we summarised the cost-effectiveness results by The 2014 US dollar value was derived by multiplying CPI
various study time windows, time horizon, net-cost savings, in 2014 at a study country by incremental costs from a
QALYs gained and ICER. Major limitations mentioned in study, divided by CPI in a study year at a study country,
each study were also summarised. and divided by a PPP exchange rate (national currency
We used a cost-effectiveness quadrant diagram to of study country per US dollar) in 2014 (ncremental
demonstrate the costs and outcomes of an IV rtPA strategy costs from a study(CPI in 2014 at a study country/CPI
compared with a non-rtPA strategy (figure2). The hori- in a study year at a study country) / PPP exchange rate).
zontal axis represents incremental QALYs associated with When a study reported multiple ICERs from different
IV rtPA and the vertical axis represents the incremental time periods, we included ICERs from both a short-term
cost associated with IV rtPA. For instance, the negative (1 year) and a long-term (30 years or a lifetime) time
numbers in the vertical axis means that cost for a patient period.
who received IV rtPA were lower than the cost for a
patient who did not receive IV rtPA. When an estimated
ICER is located in quadrant IV (lower right), IV rtPA is a RESULTS
cost-saving or a dominant strategy, thatis, higher QALYs Among 15 original articles reviewed, six studies were from
with less cost. When an estimated ICER is located in quad- the US,9 2428 two from the United Kingdom (UK),29 30 two
rant I or III, the acceptance decision depends on value of from Australia,31 32 two from China,33 34 and one each from

JooH,
 et al. Stroke and Vascular Neurology 2017;0:e000063. doi:10.1136/svn-2016-000063 3
Open Access

Canada,35 New Zealand,36 Denmark,37 and Spain.38 Nine onset of stroke with 24hours in-house MRI imaging and
of them used the payers perspective or healthcare system neurology coverage increased cost for the first and the
perspective, and four studies used the societal perspective second year after stroke.37 IV rtPA, however, became a
while two studies did not clearly mention it. dominant strategy after the third year and the 30 years
In table1, nine of 15 studies investigated the cost-effec- estimates also indicated the IV rtPA as a dominant
tiveness of IV rtPA therapy within 03hours after stroke strategy.37 Results from three non-US studies exam-
onset,9 24 26 28 30 32 35 37 38 two studies within 34.5 hours,25 27 ining the cost-effectiveness of IV rtPA within 04.5hours
three studies within 04.5 hours,31 34 36 and one study within showed that IV rtPA increased cost but was cost-effec-
06 hours29 33 (figure1). The first study that examined tive with an ICER threshold of US$50000/QALY. The
cost-effectiveness of IV rtPA was published in 1998, two UK study by Sandercock etal showed that IV rtPA within
years after the FDA approval.9 Eight out of 16 studies were 6hours of symptom onset increased cost and the ICER
published between 2011 and 2016. Among them, the five was 13 581/QALY (US$25 045/QALY in 2012) for
studies were the studies of IV rtPA within 34.5hours the first year after the stroke, but over the lifetime the
or 04.5hours after the onset of stroke.25 27 31 34 36 The therapy was a dominant strategy.29 The Chinese study
remaining three studies published during this period by Yan etalalso showed that IV rtPA within 6hours
were US studies looking at the 03hours time window increased both cost and utility and cost-effective within
to investigate up-to-date cost-effectiveness of IV rtPA24 or 14 days after the stroke.33
state specific cost-effectiveness of IV rtPA,26 and Chinese All of the ICERs were located in quadrant I or IV
study examining the 06hours cost-effectiveness of IV (figure3). Lifetime ICERs of IV rtPA within 03hours or
rtPA.33 04.5hours were located in quadrant IV, and therefore
The reviewed studies used various sources of data for using IV rtPA was a dominant strategy. The ICER of IV
analyses. Main data sources were published data or litera- rtPA within 03hours from Sinclair et al35 is not shown
ture. When published data were not available, data from in figure3 because of space limitation but the ICER was
hospitals or panel survey data were used.30 38 For economic located in quadrant IV. The ICERs from studies that
data, 10 studies used both previously published literature examined IV rtPA within 34.5hours were located in
and data from their own collection or analyses. Three quadrant I and under the threshold line, thus IV rtPA was
studies used previously published literature data only and a cost-effective strategy in this scenario. The impact of IV
two studies used data from the authors own collection or rtPA on cost in the first year was ambiguous, but IV rtPA
analyses. For clinical data, only five studies used data from was still a short-term dominant or a cost-effective strategy
both sources. In addition, three studies were from a small from most studies.
community-based study. We summarised major limitations of the literature
All studies consistently showed that IV rtPA improved (table3). The most common limitation was insufficient
QALYs (table2), even some showing marginal improve- data for accurate cost-effectiveness estimates. Some
ment of QALYs. Sinclair et al35 showed exceptionally studies mentioned a lack of generalisability because of
high improvement of QALYs associated with IV rtPA data limitations.2426 28 33 35 It was also pointed out that
(3.46 QALYs per patient). Because of the complexity of some studies used multiple data sources because of
the cost-effectiveness model and multiple input sources, limited data.24 25 Lack of long-term mortality and cost data
there could be multiple reasons of high QALYs improve- as well as insufficient up-to-date outcome and cost data
ment in this study. were also mentioned as limitations.24 26 37
The impact of IV rtPA on cost was ambiguous and varied
by time window and study time horizon. In the USA, two
of the six studies examined the cost-effectiveness of IV DISCUSSION
rtPA within the 34.5hours time window. Use of IV rtPA This review investigated studies about cost-effectiveness
within 34.5hours after the onset of stroke increased of IV rtPA for treating patients with acute ischaemic
costs (US$1495US$6050) but improved QALYs (0.24 stroke. IV rtPA within 03hours after the onset of stroke
0.28) over the lifetime. The estimated ICERs (US$6255/ was cost-saving while improving QALYs during lifetime.
QALYUS$21 978/QALY) showed the therapy was The finding about the cost-effectiveness of IV rtPA within
cost-effective using the US$50000/QALY threshold. The 03hours after the onset of stroke is consistent with
remaining four studies in the USA showed that IV rtPA previous reviews.1012 However, the most recent review was
within 03hours after onset of stroke was a dominant published before AHA/ASA released the updated guide-
strategy, thatis, cost saving and QALYs gained. lines with extended time window. In the review, we found
The results from non-US studies using IV rtPA within that IV rtPA within 04.5hours or within 34.5hours
03hours were consistent with the results from the US after the onset of stroke was cost-saving or cost-effec-
studies. One exception, which showed an ICER margin- tive. Although some studies showed that IV rtPA within
ally above an ICER threshold of US$50000/QALY at 04.5hours or within 34.5hours after the onset of stroke
the first year (US$55591/QALY), is the Danish study increased cost, it was a cost-effective strategy. The review
by Ehlers etal that examined a range of time periods results emphasise the importance of reducing door-to-
and showed that IV rtPA within 03hours after the needle time for patients with acute ischaemic stroke.

4 JooH, et al. Stroke and Vascular Neurology 2017;0:e000063. doi:10.1136/svn-2016-000063



JooH,
Table 1 Summary of model structure and main data sources used in the cost-effectiveness studies of rtPA for acute ischaemic stroke
Economic data Clinical data
Study/Year/ Data collection/ Data collection/
Country Perspective Intervention Modelling method Analyses Previous literature Analyses Previous literature
36
Te Ao et al /2015/New Health funder IV rtPA use within Simulation model No Yes Yes Yes
Zealand perspective 4.5hours after onset (TreeAge, Excel) ARCOS III
33
Yan et al /2015/China Chinese public IV rtPA use within Decision tree Yes No Yes No
health system 6hours after onset
perspective
Boudreau et al24/2014/ US payers' IV rtPA use within Decision tree, and Yes (rtPA cost) Yes No Yes
USA perspective 3hours after onset Markov model Analy$ource
(Excel)
Pan et al34/2014/China Healthcare IV rtPA use within Decision tree and Yes No Yes Yes
payers' 4.5hours after onset Markov model CNSR, CHSY TIMS-China
perspective TIMS-China
Boudreau et al25/2013/ Payers' IV rtPA use within Decision tree, and Yes Yes No Yes
USA perspective 34.5hours after Markov model Medicare
onset (Excel) reimbursement
Kazley et al26/2013/ Societal IV rtPA use within Markov model Yes No No Yes
USA (SC) perspective 3hours after onset Hospital billing,
HCUP
Tan Tanny et al31/2013/ Societal and IV rtPA use within Decision analytic Yes Yes Yes Yes

et al. Stroke and Vascular Neurology 2017;0:e000063. doi:10.1136/svn-2016-000063


Australia healthcare 4.5hours after onset model (Excel), Royal Melbourne Royal Melbourne
perspective and Monte Carlo Hospital Hospital
simulation
Tung et al27/2011/USA Societal IV rtPA use within A decision-analytic No Yes No Yes
perspective 34.5hours after model (TreeAge)
onset
Johnston28/2010/USA NA IV rtPA use within NA No Yes No Yes
3hours after onset
Ehlers et al37/2007/ NA IV rtPA use Decision tree with Yes Yes Yes Yes
Denmark within 3hours Markov model Aarhus Hospital and Aarhus Stroke
with 24hours in (TreeAge) Hvidovre Hospital Register,
house neurology data Death Register
coverageandMRI
Mar et al38/2005/Spain Societal IV rtPA use within Monte Carlo Yes Yes Yes Yes
perspective 3hours after onset simulation (4000, no Sakontzen Survey from
modelling) questionnaire and hospitals in
social service the province of
experts Gipuzkoa
Continued
Open Access

5
6
Open Access

Table 1 Continued
Economic data Clinical data
Study/Year/ Data collection/ Data collection/
Country Perspective Intervention Modelling method Analyses Previous literature Analyses Previous literature
32
Moodie et al /2004/ Healthcare IV rtPA use within MORUCOS Yes No Yes No
Australia perspective 3hours after onset NEMESIS NEMESIS
Sandercock et Healthcare IV rtPA use within Decision analysis Yes Yes No Yes
al29/2004/UK and personal 6hours after onset model (TreeAge) Western General
social services Hospital, Edinburgh
perspective
Chambers et al30/2002/ Healthcare IV rtPA use within Stroke Outcome Yes Yes No Yes
UK and social care 3hours after onset Model (TreeAge, Clinicians panels
perspective Excel)
Sinclair et al35/2001/ Healthcare IV rtPA use within Decision analytic Yes Yes No Yes
Canada system 3hours after onset model (TreeAge), Vancouver Hospital
perspective and Markov model and Health
Sciences Centre
Fagan et al9/1998/USA Healthcare IV rtPA use within Markov model Yes (rtPA cost) Yes No Yes
system 3hours after onset Seven Detroit area
perspective hospitals
ARCOS III, Auckland Regional Community Stroke Study.
CNSR, China National Stroke Registry.
CHSY, China Health Statistics Yearbook.
HCUP, Healthcare Cost and Utilization Project.
IV rtPA, intravenous recombinant tissue plasminogen activator; NA, not applicable.
MORUCOS, Model of Resource Utilization, Costs, and Outcomes for Stroke.
NEMESIS, North East Melbourne Stroke Incidence Study.
TIMS-China study, Thrombolysis Implementation and Monitor of acute ischaemic Stroke in China study.

JooH, et al. Stroke and Vascular Neurology 2017;0:e000063. doi:10.1136/svn-2016-000063



JooH,
Table 2 Main findings from the cost-effectiveness studies of rtPA for acute ischaemic stroke
Cost per QALY
Incremental cost, (ICER)
Time windows Time
Study/year/country Year of cost (hours)* horizon At year of cost 2014 US$ Incremental QALYs At year of cost 2014 US$
36
Te Ao et al /2015/New Zealand 2010 4.5 1year NZ$413 302 0.06 6641 5037
Lifetime NZ$4051 2965 0.61 5093 4860
Yan et al33/2015/China 2008 6 14 days US$569 626 0.04 14231 15652
24
Boudreau et al /2014/USA 2013 3 Lifetime (US$25000) (25421) 0.39 Dominant Dominant
((US$42500)- to (US$11000)) (0.160.66)
Pan et al34/2014/China 2011 4.5 1year US$1560 1642 0.056 27852 29315
30 years US$1000 1052 0.422 2380 2494
25
Boudreau et al /2013/USA 2011 34.5 Lifetime US$1495 1573 0.24 6255 6555
(US$4637 to US$6100) (0.010.60)
Kazley et al26/2013/USA(SC) 2010 3 6 years (US$3454) (3751) 0.425 Dominant Dominant
Lifetime (US$4084) (4435) 0.692 Dominant Dominant
Tan Tanny et al31/2013/Australia 20032011 4.5 1 year $A55.61 40 0.04 1478 991
Tung et al27/2011/USA 2010 3 to 4.5 Lifetime US$6050 6570 0.28 21978 23465
28
Johnston /2010/USA 2004 3 30 years (US$6074) (7617) 0.75 Dominant Dominant
Ehlers et al37/2007/Denmark 20042005 3 1st year US$3335 4042 0.06 55591 67370
2nd year US$433 525 0.12 3615 4373

et al. Stroke and Vascular Neurology 2017;0:e000063. doi:10.1136/svn-2016-000063


3rd year (US$2093) (2537) 0.16 Dominant Dominant
30 years (US$16561) (20073) 0.43 Dominant Dominant
Mar et al38/2005/Spain 2001 3 1 year Men: (US$7874) (10531) 0.528 Dominant Dominant
Women: (US$10496) (14038) 0.655
Moodie et al32/2004/Australia 1997 3 Lifetime (US$1496) (2207) 0.61 DALYs Dominant Dominant
Sandercock et al29/2004/UK NA 6 1 year 110 211 0.0081 13581 26018
((441) to 471) (0.00400.0183)
Lifetime (3504) (6713) 0.0363 Dominant Dominant
((4436) to (3067)) (0.03320.0848)
Chambers et al30/2002/UK 1996 3 Lifetime (2333) (4835) 0.155 Dominant Dominant
Sinclair et al35/2001/Canada 1999 3 Lifetime ($C3800) (4085) 3.46 Dominant Dominant
Fagan et al9/1998/USA 1996 3 30 years (US$4255) (6427) 0.564 Dominant Dominant
((US$13022) to (US$531)) (0.0030.850)

*Timing of patient presentation after onset of ischaemic stroke symptoms.


Numbers in parenthesis stands for negative sign.
All numbers are per patient per time horizon. 95% CIs are shown in the squared bracket.
When the IV rtPA improves QALYs and reduces cost, it is shown as 'dominant'. IV rtPA dominates not using IV rtPA. When IV rtPA is cost-effective, ICER is calculated at year of cost.
All monetary values in these two columns are consistent.
DALYs,Disability Adjusted Life Year;ICER: incremental cost-effectiveness ratio; IV rtPA, intravenous recombinant tissue plasminogen activator; QALY, quality-adjusted life year.
Open Access

7
Open Access

Figure 3 Summary of incremental cost-effectiveness ratio (ICERs) of rtPA therapy from the literature. IV rtPA, intravenous
recombinant tissue plasminogen activator; QALY, quality-adjusted life year.

In addition to time windows, some other factors may A main strength of reviewed studies is a timely research
lead to heterogeneity in study results. For example, the using the most recent available costs and outcomes from
study perspective affects the cost-effectiveness of IV rtPA. published secondary sources or primary data collection
Healthcare payers perspective considered only direct as inputs for evaluations. These inputs changed over
medical cost, while societal perspective included both time because of new medical technology for treating
direct medical cost and indirect cost, such as productivity acute ischaemic stroke and updated recommendations or
loss and informal caregiving costs. IV rtPA is expected to guidelines. After releasing the updated guidelines from
decrease indirect costs associated with stroke, while IV rtPA AHA/ASA in 2009 and other organisations in Europe
is known as reducing the short-term disability rate.79 25 and Australia on the extended time window for IV rtPA
Considering indirect costs could improve the ICER for therapy,1316 a number of publications (n=6) have exam-
IV rtPA within 34.5hours after stroke or make IV rtPA ined the extended time window in the past 6 years.
a dominant strategy. Time horizon may also significantly Some common limitations of the studies, however,
affect the cost-effectiveness of IV rtPA. All the studies were also observed. One of the main limitations in the
consistently concluded that IV rtPA increased short-term studies was that indirect costs, such as productivity loss
(1 year) cost. However, IV rtPA reduced long-term cost and informal caregiving cost, were usually not included
(lifetime or 30 years) because of lower rehabilitation and in the cost analyses. The proportion of indirect costs for
disability-associated cost among patients with IV rtPA. stroke is significant.39 A literature review showed that

8 JooH, et al. Stroke and Vascular Neurology 2017;0:e000063. doi:10.1136/svn-2016-000063


Open Access

Table 3 Major limitations listed in the cost-effectiveness studies of rtPA for acute ischaemic stroke
Study/year/country Limitations
33
Yan et al /2015/China The medical costs did not include the cost after discharge
The study used charges not real costs
The study used data from a single hospital in China
Boudreau et al24/2014/USA The results were specific to the assumptions and the data used
QALYs were derived by using multiple inconsistent studies
Long-term cost, QALYs, disabilities and mortality data were limited and dated
Pan et al34/2014/China Inaccurate estimate for each component of rtPA-associated cost
Informal caregiving costs were not included
The study did not model changes in functional status from causes other than stroke
The study used the efficacy and the utility data from studies in high-income countries
Boudreau et al25/2013/USA The results are specific to the assumptions and the data used
The data are from numerous published studies including clinical trials
Kazley et al26/2013/USA (SC) The study examined only a single state
The assumptions and data used in the study did not fully represent the clinical practise
situation
Data do not represent the current year
The study may underestimate the benefit because of previously validated model with
conservative estimates
The study only considered treatment within 3hours after stroke onset (not up to 4.5hours)
Tan Tanny et al31/2013/ The study assumed that survival and quality of life would not change between 90 days and
Australia 12 months after stroke
Efficacy data were drawn from analyses of studies of rtPA being given between 3 and
4.5hours (not rtPA within 4.5hours)
Tung et al27/2011/USA Input parameters were best estimates from previously published data
The study did not model changes in functional status from causes other than stroke
Johnston28/2010/USA The results depended on a single cost-utility analysis that required a number of uncertain
assumptions
Ehlers et al37/2007/Denmark The lack of adequate long-term data
38
Mar et al /2005/Spain The use of proxies to answer the questionnaire
Chambers et al30/2002/UK Limited published data about the cost of care for stroke survivors
Indirect costs, informal care costs and quality of life of other family members were excluded
from the model
No sufficient published information on resource use, rates of recurrence or disability and
mortality by age group
The variability of parameter estimates is not well known
Sinclair et al35/2001/Canada Short-term hospitalisation cost based on a small sample size of 22 patients from a single
centre (generalisability)
There was a difficulty in determining the costs of stroke care and services in Canada on a
per patient basis
The study used a point estimate without a formal quantitative estimate of its precision
Fagan et al9/1998/USA The study used a placebo group from the NINDS rtPA Stroke Trial as the source of data for
some aspects of the cost analysis
The protocol precluded antithrombotic therapy in the first 24hours after stroke onset, which
may affect cost and health outcomes
Three studies (Te Ao et al36 Moodie et al32 Sandercock et al29) did not list limitations.
NINDS,National Institue of Neurologic Disorders and Stroke; rtPA, intravenous recombinant tissue plasminogen activator; QALY, quality-
adjusted life year.

the median proportion of indirect costs was 32% of the current cost-effectiveness models assumed an elderly
total cost of stroke.39 However, most studies chose the cohort, productivity loss among stroke survivors may be
healthcare perspective or payers perspective, which did negligible. However, stroke onset among young adults has
not consider indirect costs. Moreover, studies using the been increasing40 and productivity loss could be a large
societal perspective did not include indirect costs,26 27 burden for young stroke survivors with disabilities. For
or included informal caregiving cost only.38 None of the better cost-effectiveness evaluation, indirect cost should
studies included productivity loss as a part of cost. When be considered as a part of cost in the analyses.

JooH,
 et al. Stroke and Vascular Neurology 2017;0:e000063. doi:10.1136/svn-2016-000063 9
Open Access

Next, most of lifetime and long-term effectiveness improve IV rtPA utilisation but require additional costs.
data, including QALYs of disabled stroke survivors, However, reviewed studies assumed that there were no
incidence of recurrent stroke among stroke survivors additional costs to provide patient access to IV rtPA.
and 1-year mortality, were limited as well as outdated, Further cost-effectiveness studies including implemen-
although all studies tried to use the most up-to-date data tation costs are needed to support utilisation of IV rtPA.
available. Most studies in the 2010 still used QALYs data
from the 1990s studies.2427 Although cost data, espe-
cially long-term cost data, could hardly be free from CONCLUSIONS
outdated data, the reviewed studies tried to use recent This study found that the IV rtPA was a dominant strategy
cost data or at least adjusted cost to current currency for those who received the therapy within 03hours after
value by using consumer price index (CPI) to alleviate the onset of stroke and a cost-effective strategy for those
concerns regarding outdated data. Lastly, there were who received the therapy within 34.5hours after stroke
some inconsistencies because of using multiple data in long-term compared with traditional treatment for
sources. For instance, QALYs by disability status were patients with acute ischaemic stroke without IV rtPA. This
not well-developed in the literature. Thus, QALYs review provides considerable support for further develop-
of disabled and non-disabled stroke survivors were ment of interventions to promote IV rtPA use. To better
obtained from different data sources.24 25 In addition, evaluate cost-effectiveness of IV rtPA, establishing relevant
most of the cost data were not collected within clinical clinical and cost data sources and developing evaluation,
trials, leading to a lack of consistency within a study. including programme costs, may be useful to improve the
Potential research areas to make up for these limita- access to and use of IV rtPA.
tions as well as to improve the quality of research Contributors HJ planned the project, performed review and wrote the manuscript.
remain. Despite robust results from sensitivity analyses, MGG helped plan the project, commented for medical issues and contributed to
developing high-quality data sources is still important revising the manuscript. GW planned and supervised the project, and contributed to
for future efforts. Developing long-term follow-up trials revising the manuscript.
among stroke survivors and research in long-term cost Competing interests None declared.
and effectiveness is most needed. Published large-scale Provenance and peer review Not commissioned; externally peer reviewed.
effectiveness data from the real-world, including cost as Open Access This is an Open Access article distributed in accordance with the
a subcomponent, and studies which investigate those Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-commercially,
data are also needed. There are needs for indirect cost and license their derivative works on different terms, provided the original work is
data and cost-effectiveness studies from the societal properly cited and the use is non-commercial. See: http://creativecommons.org/
perspective to better understand societal impact of IV licenses/by-nc/4.0/
rtPA therapy. Concurrently, better models with multiple
age cohorts would be useful to identify the impact of IV
rtPA on different age cohorts. Boudreau et al25 partly
show how much the ICER could be different by age. REFERENCES
1 Krishnamurthi RV, Feigin VL, Forouzanfar MH, et al. Global Burden
Another future research area would be to examine the of Diseases, Injuries, Risk Factors Study 2010 (GBD 2010)GBD
impact of the age or severity of stroke on ICER of IV Stroke Experts Group. Global and regional burden of first-ever
ischaemic and haemorrhagic stroke during 1990-2010: findings
rtPA treatment. from the global burden of disease study 2010. Lancet Glob Health
There were few studies in middle-income countries, 2013;1:e259e281.
2 World Health Organization. The world health report 2002. Midwifery
likely because of a lack of infrastructure to provide IV 2003;19:723.
rtPA. The incidence of stroke in the middle-income world 3 Heidenreich PA, Trogdon JG, Khavjou OA, et al. American Heart
has increased since 1970s, with 85% of stroke deaths Association Advocacy Coordinating Committee, Stroke Council,
Council on Cardiovascular Radiology and Intervention, Council on
worldwide occurring in middle-income countries.41 We Clinical Cardiology, Council on Epidemiology and Prevention, Council
found only two studies of cost-effectiveness of IV rtPA on Arteriosclerosis, Thrombosis and Vascular Biology, Council on
Cardiopulmonary, Critical Care, Perioperative and Resuscitation,
from middle-income countries.33 34 To better understand Council on Cardiovascular Nursing, Council on the Kidney in
the cost-effectiveness of IV rtPA worldwide, more studies Cardiovascular Disease, Council on Cardiovascular Surgery and
Anesthesia, and Interdisciplinary Council on Quality of Care and
from countries in Africa, Latin America and Asia would Outcomes Research. Forecasting the future of cardiovascular
be useful. disease in the united states: a policy statement from the american
In this review, we did not include studies examining heart association. Circulation 2011;123:93344.
4 Gustavsson A, Svensson M, Jacobi F, et al. CDBE2010Study
cost-effectiveness of strategies to improve the underuti- Group. Cost of disorders of the brain in Europe 2010. Eur
lisation of IV rtPA. Despite strong evidence of better Neuropsychopharmacol 2011;21:71879.
5 Truelsen T, Begg S, Mathers C. The global burden of cerebrovascular
clinical outcomes associated with IV rtPA, IV rtPA disease. 2000 http://www.who.int/healthinfo/statistics/bod_
remains underutilised among patients with acute isch- cerebrovasculardiseasestroke.pdf.
aemic stroke.42 Only 3.4%5.2% of patients with stroke 6 Jauch EC, Saver JL, Adams HP, et al. American Heart Association
Stroke Council, Council on Cardiovascular Nursing, Council
received rtPA therapy in the USA in 2009.43 Telestroke, on Peripheral Vascular Disease, Council on Clinical Cardiology.
air transport and certified stroke centres have been Guidelines for the early management of patients with acute
ischemic stroke: a guideline for healthcare professionals from the
discussed as strategies to improve the utilisation of American heart association/American stroke association. Stroke
IV rtPA. The implementation of those strategies may 2013;44:870947.

10 JooH, et al. Stroke and Vascular Neurology 2017;0:e000063. doi:10.1136/svn-2016-000063


Open Access

7 Saver JL, Gornbein J, Starkman S. Graphic reanalysis of the two 26 Kazley AS, Simpson KN, Simpson A, et al. Optimizing the economic
NINDS-tPA trials confirms substantial treatment benefit. Stroke impact of rtPA use in a stroke belt state: the case of south Carolina.
2010;41:238190. Am Health Drug Benefits 2013;6:15563.
8 Saver JL, Yafeh B. Confirmation of tPA treatment effect by baseline 27 Tung CE, Win SS, Lansberg MG. Cost-effectiveness of tissue-type
severity-adjusted end point reanalysis of the NINDS-tPA stroke trials. plasminogen activator in the 3- to 4.5-hour time window for acute
Stroke 2007;38:4146. ischemic stroke. Stroke 2011;42:225762.
9 Fagan SC, Morgenstern LB, Petitta A, et al. Cost-effectiveness of 28 Johnston SC. The economic case for new stroke thrombolytics.
tissue plasminogen activator for acute ischemic stroke. NINDS rt-PA Stroke 2010;41(10 Suppl):S59S62.
stroke study group. Neurology 1998;50:88390. 29 Sandercock P, Berge E, Dennis M, et al. Cost-effectiveness of
10 Demaerschalk BM, Hwang HM, Leung G. Cost analysis review thrombolysis with recombinant tissue plasminogen activator for
of stroke centers, telestroke, and rt-PA. Am J Manag Care acute ischemic stroke assessed by a model based on UK NHS
2010;16:53744. costs. Stroke 2004;35:14907.
11 Jung KT, Shin DW, Lee KJ, et al. Cost-effectiveness of recombinant 30 Chambers MG, Koch P, Hutton J. Development of a decision-analytic
tissue plasminogen activator in the management of acute ischemic model of stroke care in the united states and Europe. Value Health
stroke: a systematic review. J Clin Neurol 2010;6:11726. 2002;5:8297.
12 Tseng MC, Chang KC. Cost-effectiveness analysis of tissue 31 Tan Tanny SP, Busija L, Liew D, et al. Cost-effectiveness of
plasminogen activator for acute ischemic stroke: a comparative thrombolysis within 4.5 hours of acute ischemic stroke: experience
review. Acta Neurol Taiwan 2004;13:14955. from australian stroke center. Stroke 2013;44:226974.
13 Del Zoppo GJ, Saver JL, Jauch EC, et al. American Heart Association 32 Moodie ML, Carter R, Mihalopoulos C, et al. Trial application
Stroke Council. Expansion of the time window for treatment of acute of a model of resource utilization, costs, and outcomes for
ischemic stroke with intravenous tissue plasminogen activator: a stroke (MORUCOS) to assist priority setting in stroke. Stroke
science advisory from the American heart association/American 2004;35:10416.
stroke association. Stroke 2009;40:29458. 33 Yan X, Hu HT, Liu S, et al. A pharmacoeconomic assessment
14 European stroke organisation executive C, committee ESOW. of recombinant tissue plasminogen activator therapy for acute
Guidelines for management of ischaemic stroke and transient ischemic stroke in a tertiary hospital in China. Neurol Res
ischaemic attack 2008. Cerebrovasc Dis 2008;5:457507. 2015;37:3528.
15 National Stroke Foundation. Clinical guidelines for stroke 34 Pan Y, Chen Q, Zhao X, et al. TIMS-CHINA Investigators. Cost-
management 2010. Melbourne Australia, 2010. http://
effectiveness of thrombolysis within 4.5 hours of acute ischemic
strokefoundation.com.au/site/media/Clinical_Guidelines_Acute_
stroke in China. PLoS One 2014;9:e110525.
Management_Recommendations_2010.pdf.
35 Sinclair SE, Frighetto L, Loewen PS, et al. Cost-Utility analysis
16 National Institute for Health and Clincal Excellence. Alteplase
of tissue plasminogen activator therapy for acute ischaemic
for acute ischaemic stroke (NICE technology appraisal guidance
stroke: a canadian healthcare perspective. Pharmacoeconomics
[TA264], review of technology appraisal guidance 122), 2012. http://
2001;19:92736.
www.nice.org.uk/guidance/ta264/resources/ta264-stroke-acute-
36 Te Ao B, Brown P, Fink J, et al. Potential gains and costs from
ischaemic-alteplase-information-for-the-public2.
17 Robinson R. Cost-effectiveness analysis. BMJ 1993;307:7935. increasing access to thrombolysis for acute ischemic stroke patients
18 Gold MR, Stevenson D, Fryback DG. HALYS and QALYS and in New Zealand hospitals. Int J Stroke 2015;10:90310.
DALYS, oh my: similarities and differences in summary measures of 37 Ehlers L, Andersen G, Clausen LB, et al. Cost-effectiveness of
population health. Annu Rev Public Health 2002;23:11534. intravenous thrombolysis with alteplase within a 3-hour window after
19 Robinson R. Cost-utility analysis. BMJ 1993;307:85962. acute ischemic stroke. Stroke 2007;38:859.
20 Eichler HG, Kong SX, Gerth WC, et al. Use of cost-effectiveness 38 Mar J, Begiristain JM, Arrazola A. Cost-effectiveness analysis of
analysis in health-care resource allocation decision-making: how thrombolytic treatment for stroke. Cerebrovasc Dis 2005;20:193200.
are cost-effectiveness thresholds expected to emerge? Value Health 39 Joo H, George MG, Fang J, et al. A literature review of indirect costs
2004;7:51828. associated with stroke. J Stroke Cerebrovasc Dis 2014;23:175363.
21 Grieve R, Hutton J, Bhalla A, et al. A comparison of the costs and 40 Kissela BM, Khoury JC, Alwell K, et al. Age at stroke: temporal
survival of hospital-admitted stroke patients across Europe. Stroke trends in stroke incidence in a large, biracial population. Neurology
2001;32:168491. 2012;79:17817.
22 The world bank. http://data.worldbank.org/indicator/FP.CPI.TOTL. 41 Feigin VL, Krishnamurthi R. Stroke prevention in the developing
23 Organisation for Economic Co-operation and Development. https:// world. Stroke 2011;42:36558.
stats.oecd.org/Index.aspx?DataSetCode=SNA_TABLE4. 42 Chapman SN, Mehndiratta P, Johansen MC, et al. Current
24 Boudreau DM, Guzauskas GF, Chen E, et al. Cost-effectiveness of perspectives on the use of intravenous recombinant tissue
recombinant tissue-type plasminogen activator within 3 hours of plasminogen activator (tPA) for treatment of acute ischemic stroke.
acute ischemic stroke: current evidence. Stroke 2014;45:30329. Vasc Health Risk Manag 2014;10:7587.
25 Boudreau DM, Guzauskas G, Villa KF, et al. A model of cost- 43 Adeoye O, Hornung R, Khatri P, et al. Recombinant tissue-type
effectiveness of tissue plasminogen activator in patient subgroups plasminogen activator use for ischemic stroke in the united states:
3 to 4.5 hours after onset of acute ischemic stroke. Ann Emerg Med a doubling of treatment rates over the course of 5 years. Stroke
2013;61:4655. 2011;42:19525.

JooH,
 et al. Stroke and Vascular Neurology 2017;0:e000063. doi:10.1136/svn-2016-000063 11